The long-term objective of this Phase II SBIR proposal is to develop targeted microbubbles in conjunction with ultrasound for the treatment of vascular thrombosis (Sonothrombolysis). Gas-filled microbubbles are currently used as vascular ultrasound diagnostic agents because of their exquisite ability to reflect sound. In addition, recent pre-clinical studies have demonstrated that ultrasound-mediated cavitation of microbubbles has utility in lysing platelet thrombi (clots). During the Phase I period, we have developed targeted microbubble agents and have demonstrated; 1) binding to thrombi in the mouse cremasteric artery model and 2) lysing thrombi in vitro more efficiently than non-targeted microbubbles. The research in the Phase II period of the grant will involve 5 parts: 1) synthesize bioconjugate ligands selective for the GP IIb/llla receptor on activated platelet thrombi, 2) develop microbubble formulations with shell membranes that possess efficient cavitational force for clot lysis, 3) undertake ultrasound physics studies to optimize cavitation of microbubbles for efficient ultrasound-mediated thrombolysis, 4) conduct preclinical studies in the occluded rabbit femoral artery model to determine safety and efficacy of targeted microbubbles and ultrasound using parameters based upon objectives 2) and 3), 5) perform pre-clinical studies in the left anterior descending (LAD) or left circumflex branch occlusion model in pigs examining safety and efficacy of ultrasound-mediated targeted microbubble thrombolysis therapy, and 6) perform CMC and stability studies. We hypothesize that ultrasound-mediated targeted microbubble therapies will offer efficient, less invasive, and safer alternatives to thrombolytic agents or emergency thrombectomies. Furthermore, ultrasound mediated therapies will provide affordable treatments that can be used in small hospitals and emergency rooms where expensive treatment is prohibitive.